WO2019026342A1

WO2019026342A1 - Medical sheet

Info

Publication number: WO2019026342A1
Application number: PCT/JP2018/013402
Authority: WO
Inventors: 誠澤田; 清治星野
Original assignee: 株式会社多磨バイオ
Priority date: 2017-08-01
Filing date: 2018-03-29
Publication date: 2019-02-07
Also published as: TWI675054B; JP2019025824A; JP6263305B1; TW201910400A

Abstract

[Problem] To provide a medical sheet with which a surface (a portion) subjected to ion bombardment, and a surface (a portion) which has not been subjected to ion bombardment can be distinguished from each other. [Solution] When Δb refers to the difference between value b1, which is the b value of a roughened surface portion 3, and value b2, which is the b value of a second surface 7, this medical sheet has a Δb in the range of 2-11 inclusive. A production method for the medical sheet includes a surface roughening step in which ion bombardment is used to perform surface roughening treatment on a portion or the entirety of a first surface 5 of a sheet including polytetrafluoroethylene, to form a roughened surface portion 5. In the production method, the ion bombardment is performed continuously at a degree of vacuum in the range of 10-7 to 10-1 atmospheres inclusive.

Description

Medical seat

The present invention relates to a medical seat. More specifically, the present invention relates to a medical sheet that can be used as a biorepair material, an artificial membrane, or the like.

Patents 4445697 and 550 5752 disclose biorepair materials.

Patent 4445697 Patent No. 5505752

The biorepairing material described in the above-mentioned publication is indistinguishable between the surface to which the ion bombardment is applied and the surface which is not. Biorepair materials and artificial membranes are implanted into living organisms. For this reason, it is difficult to use coloring agents, and it is necessary to re-approve approval once the composition changes. For this reason, the medical sheet which can distinguish the field (part) to which ion impact was given, and the field (part) to which ion impact was not given was desired. Furthermore, when an artificial blood vessel is prepared using a medical sheet, one which is easy to establish vascular endothelial cells is desired.

In the present invention, basically, the whole or a part of one surface of a resin sheet such as ePTFE (expanded polytetrafluoroethylene) is subjected to a surface roughening treatment by ion impact or the like and then subjected to a heat treatment, It is based on the knowledge that only the part subjected to the surface roughening treatment changes color without changing the physical properties. In addition, the present invention maintains the vacuum degree of the ion bombardment device at a constant value when performing ion bombardment, and continuously performs ion bombardment to enhance the effect of ion bombardment and achieve high surface roughening. Based on the finding that it can be achieved.

The present invention relates to a medical seat. This medical sheet is a medical sheet 1 having a first surface 5 having a roughened portion 3 and a second surface 7 opposite to the first surface 5 and containing polytetrafluoroethylene. .
The roughened portion 3 has an Rz value which is a surface roughness value of 8 or more and 14 or less, and an Ra value of 0.65 or more and 1.5 or less. The roughened portion 3 is preferably a portion modified by the ion bombardment portion. The roughened portion 3 may be part of the first surface 5 or may be the entire first surface 5. B ₁ value and a b value of roughening unit 3, the difference between the b ₂ values is b value of the second surface 7 when the [Delta] b, [Delta] b are those preferably 2 to 11.

The present invention also provides a method of manufacturing a medical sheet. This method comprises a roughening step of roughening the whole or part of the first surface 5 of the sheet containing polytetrafluoroethylene by ion bombardment to form a roughened portion 5 It is a manufacturing method. And ion bombardment is continuously performed at a degree of vacuum of 10 ^-7 atm or more and 10 ^-1 atm or less. Preferably, the method further comprises the step of heating the sheet containing polytetrafluoroethylene that has undergone the surface roughening step to obtain a medical sheet. The roughened portion 3 preferably has an Rz value which is a surface roughness value of 8 or more and 14 or less and an Ra value of 0.65 or more and 1.5 or less. An example of the heating step is a step of heating the sheet at a temperature of 60 ° C. or more and 300 ° C. or less for 10 seconds or more and 10 minutes or less.

According to the present invention, a medical sheet capable of producing a medical sheet capable of distinguishing between a surface (part) to which ion bombardment is applied and a surface (part) not subjected to surface roughening treatment, and a distinguishable medical sheet Can provide Moreover, when an artificial blood vessel was created using this medical sheet, the vascular endothelial cells were easily fixed.

FIG. 1 is a conceptual view showing a medical sheet of the present invention. FIG. 1 (a) shows the first surface, and FIG. 1 (b) shows the second surface.

Hereinafter, an embodiment of the present invention will be described using the drawings. The present invention is not limited to the embodiments described below, and includes those appropriately modified by the person skilled in the art from the following embodiments within the obvious scope.

The present invention relates to a medical seat. Medical sheet means a sheet that has a part with high adhesion and adhesion to living tissue and a low part and can be used in medical treatment. This sheet can be used, for example, to adhere to a specific tissue while the opposite side does not adhere to the tissue. In addition, it is possible to obtain an artificial blood vessel by rolling the medical sheet. Furthermore, the medical sheet can be used for artificial valves and various transplants by cutting it into a predetermined shape. The medical sheet may be a biorepair material described in Japanese Patent No. 4445697, or may be a filling material having adhesiveness to an artificial dura mater or muscle described in Japanese Patent No. 5505752. These most preferred materials are elliptical in size ranging from 7.5 cm x 10.0 cm to 26.0 cm x 34.0 cm. Other planar shapes are also envisioned for use in the present invention, such as circles, squares, triangles, and shapes specifically adapted to fit. Regardless of the shape, the size range of suitable implantable sheet material is small from 1.0 cm x 1.0 cm to large 50.0 cm x 50.0 cm, 5.0 cm x 5.0 cm to 40 Small pieces of a size of 0 cm × 40.0 cm are preferred, and may be small pieces ranging from 7.0 cm × 7.0 cm to 20.0 cm × 20.0 cm.

As shown in FIG. 1, this medical sheet 1 has a first surface 5 having a roughened portion 3 and a second surface 7 opposite to the first surface 5. It is a medical sheet 1 containing fluoroethylene. FIG. 1 is a conceptual view showing a medical sheet of the present invention. FIG. 1 (a) shows the first surface, and FIG. 1 (b) shows the second surface. The roughened portion 3 means a portion whose surface roughness is rougher than that of the second surface. The roughened portion 3 may be a portion modified by ion bombardment. The roughened portion 3 may be the entire first surface 5 or may be a specific portion of the first surface. When it is desired to roughen only a specific part of the first surface, for example, the roughening treatment may be applied while masking the part not to be roughened. The roughened portion 3 has an Rz value of 8 or more and 14 or less (preferably, 9 or more and 13 or less, or 9.5 or more and 12.5 or less, or 10 or more and 12 or less) which is a value of surface roughness, and an Ra value May be 0.65 or more and 1.5 or less (preferably 0.7 or more and 1.4 or less, or 0.8 or more and 1.3 or less). These values may be determined in accordance with JIS B 0601-2001.

The medical sheet having such surface roughness has a different degree of color change between the roughened portion and the non-smoothed portion by heat treatment, and therefore, it is for medical use having the roughened portion and the non-smoothed portion You can get a sheet. In addition, as described later, when an artificial blood vessel is manufactured using a medical sheet having the above-mentioned surface roughness, vascular endothelial cells are easily fixed.

It is preferable that the medical sheet is capable of visually discriminating the roughened portion and the non-roughened portion based on the difference in color.

The Lab color specification method can be obtained from the following equation using tristimulus values X, Y and Z defined in JIS Z8730.

L = 10 Y ^1/2 (1)
a = 17.5 (1.02X-Y) / Y ^1/2 ... (2)
b = 7.0 (Y-0.847 Z) / Y ^1/2 ... (3)
L: Lightness index in color difference formula of Hunter (R.S. Hunter).
a, b: color coordinates in the color difference formula of the hunter.
X, Y, Z: values of tristimulus values X, Y, Z in the X, Y, Z color specification.

In the Lab color specification, L represents lightness, and is generally a value from 100 to 0. Lightness refers to the condition of light and shade of color, that is, the degree of lightness. The larger this L value, the brighter it means.

In addition, a and b represent colors, a value represents red-green direction and b value represents yellow-blue direction. Therefore, the redness becomes stronger as the a value becomes larger, the greenness becomes stronger as it becomes smaller, the yellowness becomes stronger as the b value becomes larger, and the blueness becomes stronger as the b value becomes smaller.

Then, when the difference between the b value of the roughened portion 3 and the b2 value of the second surface 7 is Δb, this medical sheet has Δb of 2 or more and 11 or less. is there. Δ b is usually obtained by b 1 value −b 2 value. Δb may be 4 or more and 10 or less, Δb may be 5 or more and 9.5 or less, Δb may be 6 or more and 9.5 or less, and Δb may be 6 or more and 9 or less, Δb may be 7 or more and 8.5 or less. Thus, the medical sheet of the present invention can be distinguished from the surface having the roughened portion and the surface not having the roughened portion since the roughened portion has a yellowish color (note that both surfaces are not provided) Both parts may have a roughened part, and it may be possible to judge whether the part is a roughened part or not by the color of the roughened part).

The medical sheet can also be distinguished by the roughened part exhibiting a slightly reddish color. In particular, under a yellow fluorescent lamp, in order to determine the roughened portion, it is possible to distinguish between reddish and greenish. The conventional medical sheet has a slightly greenish color. On the other hand, the medical sheet of the present invention exhibited a slightly reddish color. This medical sheet has Δa of 0.1 or more and 1 or less, where Δa is the difference between the a1 value of the roughened portion 3 and the a2 value of the second surface 7. Is preferred. Δa is usually determined by the a1 value−a2 value. Δa may be 0.15 or more and 0.9 or less, or Δa may be 0.2 or more and 0.5 or less.

An example of polytetrafluoroethylene is expanded polytetrafluoroethylene (ePTFE). An example of expanded polytetrafluoroethylene is expanded porous polytetrafluoroethylene made according to U.S. Pat. Nos. 3,953,566 and 4,187,390. In the examples, basically, experiments were conducted using expanded polytetrafluoroethylene. On the other hand, the effects demonstrated in the examples are considered to be effective for all sheets of polytetrafluoroethylene.

Next, the present invention relates to a method of manufacturing a medical sheet. This method is
The surface roughening process which roughens all or one part of 1st surface 5 of the sheet | seat containing a polytetrafluoroethylene, and forms the roughening part 5 is included. Then, in the surface roughening step, ion bombardment is continuously performed at a degree of vacuum of 10 ⁻⁷ atmosphere or more and 10 ⁻¹ atmosphere or less. The method may include the steps of heating the sheet containing polytetrafluoroethylene that has undergone the surface roughening step to obtain a medical sheet. Conventionally, the surface of the sheet has been washed with an organic solvent. On the other hand, when the surface of the sheet was washed with an organic solvent, the organic solvent remained on the surface of the sheet, and the compound derived from the organic solvent was adhered to the surface of the sheet. For this reason, in the present invention, it is preferable to perform the operations of cutting the sheet and roughening the sheet in a clean room and not washing the sheet surface with the organic solvent. The ion bombardment is preferably performed continuously in a vacuum chamber as described later.

Examples of roughening treatment in the roughening process are ion implantation (ion bombardment), plasma treatment, corona treatment, UV treatment, chemical blast and sand blast. In this manufacturing method, the Rz value which is the surface roughness value of the roughened portion 3 may be 8 or more and 14 or less, and the Ra value may be 0.65 or more and 1.5 or less. That is, it is preferable to carry out the next processing step in a state where the surface is slightly roughened compared to the conventional medical sheet. For ion implantation, for example, in the conventional ion implantation method, the degree of vacuum in the vacuum chamber (in the ion bombardment apparatus) during ion bombardment is kept within a certain range, and ion bombardment is continuously performed; By controlling the amount of ion bombardment in the y-axis direction, desirable surface roughness can be achieved. An example of the ion density (dose amount φ) is 1 × 10 ¹³ ions / cm ² or more and 1 × 10 ¹⁶ ions / cm ² or less, and 1 × 10 ¹⁴ ions / cm ² or more and 1 × 10 ¹⁵ ions / cm ² or less May be. An example of the acceleration voltage of ions is 30 keV or more and 2000 keV or less, 70 keV or more and 300 keV or less, or 100 keV or more and 250 keV or less. The example of ion irradiation time is 1 minute or more and 5 hours or less, 10 minutes or more and 2 hours or less may be sufficient, and 30 minutes or more and 1 hour or less may be sufficient.

An example of the degree of vacuum in the chamber is 10 ^-7 atm or more and 10 ^-1 atm or less, 10 ^-6 atm or more and 10 ^-2 atm or less, or 10 ^-5 atm or more and 5 × 10 ^-3 atm or less And 10 ^-4 atm or more and 10 ^-3 atm or less. The vacuum system itself is known, and the desired degree of vacuum can be achieved by using a vacuum system comprising a vacuum chamber and a pump connected to the vacuum chamber. By performing ion bombardment while properly exhausting, ion bombardment can be performed continuously. It is considered that good surface roughness was achieved by this. Further, it is preferable to control the ion irradiation amount so as to be uniform in the x-axis direction and the y-axis direction. For this purpose, the position and direction of the ion irradiation nozzle may be controlled. In this way, desirable surface roughness can be achieved. For example, after the surface roughness is controlled in such a state, heat treatment may be performed to make the medical sheet more yellowish.

Examples of surface modification of PTFE include introducing a functional group on the surface of the substrate and etching the surface using O ₂ or Ar gas, polymerizing an organic monomer under plasma, and forming a thin film on the surface of the substrate It is a plasma polymerization method to form.

The heating step may be a step of heating the sheet at a temperature of 60 ° C. or more and 300 ° C. or less for 10 seconds or more and 1 hour or less. The heating temperature may be, for example, 60 ° C. or more and 150 ° C. or less, or 100 ° C. or more and 130 ° C. or less. In particular, when ethylene oxide gas (EOG) sterilization is performed, the temperature may be 60 ° C. or more and 100 ° C. or less, or 65 ° C. or more and 80 ° C. or less. The heating temperature may be 110 ° C. or more and 140 ° C. or less, or 110 ° C. or more and 130 ° C. or less. The heating time may be appropriately adjusted according to the heating temperature, and may be 10 minutes to 45 minutes, may be 15 minutes to 30 minutes, or may be 20 seconds to 5 minutes, or 40 seconds to 2 minutes. Or less. After cooling the sheet that has undergone the heating process, the difference between b1 of the roughened portion 3 and b2 of the second surface 7 opposite to the first surface 5 is Δb and b Preferably, the sheet is heated such that Δb is 2 or more and 11 or less.

In a clean room, Gore-Tex (registered trademark), a Gore ePTFE, was cut into a size of 10 cm × 10 cm to obtain an ePTFE sheet. The surface of the ePTFE sheet was subjected to ion bombardment using an ion implantation apparatus without cleaning the surface with an organic solvent, and the surface was modified. The conditions of ion bombardment were as follows.
Ion: Ar ⁺
Energy: 150 KeV
Ion density: 5 × 10 ¹⁴ ions / cm ²

During the ion bombardment, the degree of vacuum in the ion implantation apparatus was maintained at 10 ^{-5 at} least 10 ^-4 atm. Also, the ion irradiation amount was adjusted so that the ion bombardment was uniform in the x-axis direction and y-axis direction of the sheet.

The surface-modified ePTFE sheet was heat-treated in an autoclave (120 ° C.) for 20 minutes. After heating with an autoclave, the ePTFE sheet was allowed to stand until it became normal temperature. Thus, a medical sheet was obtained.

[Reference Example 1]
A medical sheet was obtained in the same manner as in Example 1 except that heating with an autoclave was not performed (Reference Example 1).

The surface roughness of the obtained medical sheet was measured. The surface roughness was determined using an Olympus 3D measurement laser microscope OLYMPUS OLS4000. The obtained results are shown in Table 1.

The color tone of the obtained medical sheet was measured. For the measurement of color tone, a spectrophotometer manufactured by Konica Minolta Co., Ltd. was used. The obtained results are shown in Table 2.

As a result of visual observation, the portion to which the ion bombardment was applied was clearly yellowish as compared with the reference example 1, and it was possible to clearly distinguish the presence or absence of the ion bombardment.

Example 2
A medical sheet was obtained in the same manner as in Example 1 except that the temperature of the autoclave was 130 ° C.

[Example 3]
A medical sheet was obtained in the same manner as in Example 1 except that the autoclave time was 3 minutes.

Example 4
A medical use sheet was obtained in the same manner as in Example 1 except that a PTFE sheet was used instead of the ePTFE sheet.

[Example 5]
A medical sheet was obtained in the same manner as in Example 1 except that the roughened portion was partially formed.

[Example 6]
A medical sheet was obtained in the same manner as in Example 1 except that sandblasting was used instead of ion implantation.

[Example 7]
A medical sheet was obtained in the same manner as in Example 1 except that plasma etching was performed instead of ion implantation.

[Example 8]
A medical sheet was obtained in the same manner as in Example 1 except that EOG sterilization at 70 ° C. was performed instead of the autoclave.

[Example 9]
A medical sheet was obtained in the same manner as in Example 1 except that POREFLON (registered trademark) manufactured by Sumitomo Electric Co., Ltd. was used instead of Gore-Tex (registered trademark) manufactured by Gore ePTFE.

In Examples 2 to 7 and 9, those closer to those in Example 1 became yellowish, but those in Example 1 were the most yellow and it was possible to clearly grasp the presence or absence of the treatment. The product of Example 8 was slightly yellowish as compared with the product of Reference Example 1, and the presence or absence of the treatment could be grasped by careful observation. Also, when the same experiment was conducted by changing the ion bombardment conditions in Example 1 variously, the same tendency as in the above Examples 1 to 9 and Reference Example 1 was shown.

Comparative Example 1
The medical sheet was prepared according to the conditions actually performed about the example of patent 4445697.
The surface of expanded polytetrafluoroethylene (ePTFE) was washed with an organic solvent. Thereafter, the ion beam was irradiated (Ne ⁺ , 150 keV, 5 × 10 ¹⁴ ions / cm ² ) at 200 KeV. Since the degree of vacuum drops every time the ion bombardment is performed, the operation of stopping the ion bombardment and the ion bombardment and performing the evacuation is repeated. Also, the uniformity in the direction of ion bombardment was not adjusted. The color tone of the obtained medical sheet was measured. For the measurement of color tone, a spectrophotometer manufactured by Konica Minolta Co., Ltd. was used.

As for the surface roughness of the medical sheet obtained in Comparative Example 1, the Rz value was an average of 5 (standard deviation 0.5), and the Ra value was an average of 0.52 (standard deviation 0.05). . This sheet could not distinguish the color of the surface irradiated with the ion beam and the surface not irradiated. The average b value of the roughened portion of this sheet is considered to be a negative value.

[Example 10]
The medical sheet obtained in Comparative Example 1 was heat-treated at an autoclave (120 ° C.) for 20 minutes. After heating with an autoclave, the ePTFE sheet was allowed to stand until it reached normal temperature. Thus, a medical sheet was obtained. As a result of visual observation, the portion subjected to the ion bombardment had a tint so as to be slightly distinguishable as compared with the comparative example 2. The b value of this sheet was about 2 to 3.

An artificial blood vessel (medical tube) having an inner diameter of 4 mm and 6 mm was prepared using the sheets in the above-described Examples, Reference Examples, and Comparative Examples. The coagulation components of blood when human whole blood flowed into the created artificial blood vessel for 1, 2, 4, 8, 24, 48 hours were observed. As a result, in the case of Example 1, a thrombus membrane was formed at an extremely early stage, and vascular endothelial cells were fixed on the thrombus membrane, resulting in a good artificial blood vessel. On the other hand, although the thing of the comparative example 1 does not have a leak etc. of blood and it functions as an artificial blood vessel, it took a long time until a vascular endothelial cell settles. The other examples and reference examples exhibited the performance between Example 1 and Comparative Example 1.

The present invention can be utilized in the field of medical devices.

1 medical sheet, 3 roughened portion, 5 first surface, 7 second surface

Claims

A medical sheet (1) having a first surface (5) having a roughened portion and a second surface (7) opposite to the first surface (5) and containing polytetrafluoroethylene There,
The medical sheet according to the present invention, wherein the roughened portion (3) has an Rz value which is a surface roughness value of 8 or more and 14 or less and an Ra value of 0.65 or more and 1.5 or less.
The medical sheet according to claim 1, wherein the roughened portion (3) is a portion modified by an ion bombardment portion.
The medical sheet according to claim 1, wherein the roughening portion (3) is a part of the first surface (5).
A medical sheet according to claim 1, wherein b 1 value and a b value of roughening portion (3), the difference between the b 2 values is b value of the second surface (7) [Delta] b And a medical sheet having a Δb of 2 or more and 11 or less.
A medical sheet comprising a roughening step of roughening a whole or a part of a first surface (5) of a sheet containing polytetrafluoroethylene by ion bombardment to form a roughened portion (5) A manufacturing method,
The method is characterized in that the ion bombardment is performed continuously at a degree of vacuum of 10 -7 atm or more and 10 -1 atm or less.
A method of manufacturing a medical sheet according to claim 5,
Heating the sheet comprising the polytetrafluoroethylene that has undergone the surface roughening step to obtain a medical sheet.
A method of manufacturing a medical sheet according to claim 5,
The surface-roughened portion (3) has a surface roughness value Rz value of 8 or more and 14 or less, and an Ra value of 0.65 or more and 1.5 or less.
A method of manufacturing a medical sheet according to claim 5,
The heating step is a step of heating the sheet at a temperature of 60 ° C. to 300 ° C. for 10 seconds to 10 minutes.